Exome sequencing revealed a splice site variant in the IQCE gene underlying post-axial polydactyly type A restricted to lower limb

Abstract

Polydactyly is characterized by an extra supernumerary digit/toe with or without bony element. To date variants in four genes GLI3, ZNF141, MIPOL1 and PITX1 have been implicated in developing non-syndromic form of polydactyly. The present study involved characterization of large consanguineous family of Pakistani origin segregating post-axial polydactyly type A, restricted to lower limb, in autosomal recessive pattern. DNA of two affected members in the family was subjected to exome sequencing. Sanger sequencing was then followed to validate segregation of the variants in the family members. A homozygous splice acceptor site variant (c.395-1G>A) was identified in the IQCE gene, which completely co-segregated with post-axial polydactyly phenotype within the family. The homozygous variant was absent in different public variant databases, 7000 in-house exomes, 130 exomes from unrelated Pakistani individuals and 215 ethnically matched controls. Mini-gene splicing assay was used to test effect of the variant on function of the gene. The assay revealed loss of first nucleotide of exon 6, producing a -1 frameshift and a premature stop codon 22 bases downstream of the variant (p.Gly132Valfs*22). The study provided the first evidence of involvement of the IQCE gene in limbs development in humans.

A novel homozygous sequence variant in GLI1 underlies first case of autosomal recessive pre‐axial polydactyly

“…Based on the location of an extra digit, polydactyly is subdivided into three types including post‐axial, mesoaxial, and pre‐axial polydactyly . Genetically, five genes including ZNF141 , IQCE , ZRS/SHH , GLI1 , GLI3 , FAM92A , and three other loci mapped on chromosome 13q21‐32, 13q13.3‐21.2, and 19p13.1‐13.2 have been associated with nonsyndromic form of post‐axial polydactyly . Clinically, pre‐axial polydactyly is featured by duplication of thumb.…”

Whole‐exome sequencing revealed a nonsense mutation in STKLD1 causing non‐syndromic pre‐axial polydactyly type A affecting only upper limb

“…9 Screening of the variants was based presence of polydactyly phenotypes in affected members as described previously (Table S1). The protocol followed was the same as described previously.…”

“…[8][9][10] In addition, variants inactivating GLI1 causing overlapping Ellis-Van Creveld syndrome and post-axial polydactyly (PAP) have been reported as well. [8][9][10] In addition, variants inactivating GLI1 causing overlapping Ellis-Van Creveld syndrome and post-axial polydactyly (PAP) have been reported as well.…”

“…Recently, three genes including ZNF141 causing PAP type A6, IQCE causing PAP type A7 and FAM92A causing PAPA have been reported. [8][9][10] In addition, variants inactivating GLI1 causing overlapping Ellis-Van Creveld syndrome and post-axial polydactyly (PAP) have been reported as well. 11 In the present study, we have investigated two families segregating non-syndromic PPD in autosomal recessive manner.…”

FAM92A Underlies Nonsyndromic Postaxial Polydactyly in Humans and an Abnormal Limb and Digit Skeletal Phenotype in Mice

“…(8,9) Only three causal genes, GLI3 (PAPA1), (10) ZNF141 (PAPA6), (9) and IQCE (PAPA7), (11) have been identified. Variants in GLI3 are associated with both PAPA and PAPB, even within the same family.…”